Referring to FIG. 1, isolated in only small amounts from the Britannia marine tunicate Dendrodoa grossularia (Styelidae), grossularine-1 1 represents one of the more structurally intriguing members of a relatively small but potent class of α-carboline metabolites that exhibit pronounced effects against solid human tumor cell lines.[1] Closely related to grossularine-1 1 is N,N-didesmethylgrossularine-1 2 (from the Chuuk Atoll tunicate Polycarpa aurata) whose structure was established by X-ray crystallographic analysis.[2]
In contrast to the well-known class of β-carboline-derived natural products, grossularines represent the first examples of naturally occurring α-carbolines. Despite the promising biological activity of grossularine-1 1, only one total synthesis has been completed.[3] In Hibino's approach, the construction of the tetracyclic pyrido[2,3-b]indole ring system proceeded in a linear manner through the use of Pd-catalyzed cross-coupling reactions of halogenated indoles and metallated imidazoles. A formal synthesis of grossularine-1 1 has been reported by Molina that intersects Hibino's key intermediate.[4] The limited material available from nature as well as synthetic sources, however, have hampered further investigations in vivo.
Accordingly, improved methods for the synthesis of grossularine-1 1 and N,N-didesmethylgrossularine-1 2 and methods for use of said compounds are desired.